KELFER

Be sure to always take this medication carefully and exactly follow your doctor's instructions.

Check with your doctor or pharmacist if in doubt.

The dose of DEFERIPRONE

ARROW 500 mg, film-coated scored tablet to take depends on your weight.

The recommended dose is 25 mg/kg, 3 times per day, or a total daily dose of 75 mg/kg. The total daily dose should not exceed 100 mg/kg. Take your first dose in the morning, your second dose at midday, and your third dose in the evening.

ARROW 500 mg, film-coated tablet can be taken with or without food; However, you may be reminded to take DEFERIPRONE ARROW 500 mg, film-coated scored tablet more easily if you take it with your meals.

If you take more DEFERIPRONE

ARROW 500 mg, scored film-coated tablet than you should

If you have, by accident, more than the dose prescribed, you must contact your doctor.

If you forget to take DEFERIPRONE

ARROW 500 mg, scored film-coated tablet

If you miss a dose, take it again as soon as you remember and take the next dose at the usual time.

If you miss more than one dose, do not take a double dose to make up for the dose you forgot to take, but be happy to resume the dosing schedule we no rmal.

Do not change the dose you take daily without first consulting your doctor.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

This medicine does not require any special storage precautions.

Pharmacotherapeutic group: all other drugs, iron chelating agents.

• ATC code: V03AC02.

ARROW 500 mg, scored film-coated tablet contains the active substance deferiprone.

ARROW 500 mg, film-coated scored tablet is an iron chelator, a type of medication that helps remove excess iron from the body.

ARROW 500 mg, scored film-coated tablet is used to treat iron load caused by frequent blood transfusions in patients with thal as Major illness when current chelation treatment is contraindicated or unsuitable.

Deferiprone is a chelating agent with an affinity for ferric ions (iron III).

Deferiprone binds with ferric ions to form neutral 3:1 (deferiprone:iron) complexes that are stable at physiological pH. 12.2 Pharmacodynamics No clinical studies were performed to assess the relationship between the dose of deferiprone and the amount of iron eliminated from the body.

At the maximum approved recommended dose, deferiprone does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Deferiprone Tablets (three times a day), 1,000 mg and 500 mg The mean C max and AUC of deferiprone was 20 mcg/mL and 50 mcg∙h/mL, respectively, in healthy subjects.

The dose proportionality of deferiprone over the approved recommended dosage range is unknown.

Deferiprone appeared in the blood within to 10 minutes after oral administration.

Peak serum concentration of deferiprone was reached approximately to 2 hours after a single dose.

No clinically significant differences in the pharmacokinetics of deferiprone were observed following administration with food.

The elimination half-life of deferiprone is approximately 2 hours.

Metabolism Deferiprone is metabolized primarily by

The major metabolite of deferiprone is the 3.

• O -glucuronide, which lacks iron binding capability.

Following oral administration, 75% to 90% of the administered dose was recovered in urine (primarily as metabolite) in the first 24 hours.

No clinically significant differences in the pharmacokinetics of deferiprone were observed based on sex, race/ethnicity, body weight, mild to severe (eGFR to 89 mL/min/1.73 m 2 ) renal impairment, or mild (Child Pugh Class A) to moderate (Child Pugh Class B) hepatic impairment.

The effect of age, including geriatric or pediatric populations, end stage renal disease or severe (Child Pugh Class C) hepatic impairment on the pharmacokinetics of deferiprone is unknown.

UGTIA6 Inhibitors: Phenylbutazone (UGT1A6 inhibitor) decreased glucuronidation of deferiprone by up to 78%.

Deferiprone has the potential to bind polyvalent cations (e.g., iron, aluminum, and zinc).

Pharmacotherapeutic group: all other drugs, iron chelating agents, ATC code: V03AC02 The active substance is deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one), a ligand which combines iron in a molar ratio of 3:1. p ha r m acod y na miceffe ts Clinical studies have demonstrated that deferiprone promotes iron excretion, with a total dose of 75 mg/kg per day being able to prevent the progression of iron accumulation, as assessed by serum ferritin level, in blood transfusion-dependent thalassemia patients.

Data from the published literature regarding studies of iron status in patients with thalassemia major show that the use of deferiprone in conjunction with deferoxamine (administration of both chelators in the same day, whether at the same time or consecutively, for example, deferiprone during the day and deferoxamine at night), results in greater iron excretion than the use of either drug alone.

Deferiprone doses in these studies ranged from 50-100 mg/kg/day and deferoxamine doses from 40-60 mg/kg/day. However, chelation therapy may not protect against iron-induced organ damage.

Clinical efficacy studies were carried out with film-coated tablets dosed at 500 mg. Studies LA16-0102, LA-01, and LA08-9701 compared the effectiveness of deferiprone with deferoxamine in controlling serum ferritin in patients with transfusion-dependent thalassemia.

Both deferiprone and deferoxamine similarly lead to a marked stabilization or reduction in body iron burden, despite continuous iron transfusion administration in these patients (no difference in the proportion of patients with a negative trend in serum ferritin level between the two treatment groups by regression analysis; p > 0.05).

A T2* weighted MRI (Magnetic Resonance Imaging) method was also used to quantify myocardial iron load.

Iron overload causes a concentration-dependent loss of MRI T2 signal, therefore increased myocardial iron load reduces myocardial MRI T2 values.

T2* values ​​less than 20 ms indicate cardiac iron overload.

An increase in MRI

T2* values ​​under treatment indicates that iron is being removed from the heart.

A positive correlation between MRI

T2* values ​​and cardiac function (as measured by Ventricular Ejection Fraction (VEF)) has been documented.

LA16-0102 compared the effectiveness of deferiprone with deferoxamine in reducing cardiac iron overload and improving cardiac function (as measured by FEV) in patients with transfusion-dependent thalassemia.

Sixty-one patients with cardiac iron overload, previously treated with deferoxamine, were randomized to continue taking deferoxamine (at a mean dose of 43 mg/kg/day; N = 31) or to switch to deferiprone (at a mean dose of 92 mg/kg/day; N = 29).

Over the 12-month study period, deferiprone was superior to deferoxamine in reducing cardiac iron load.

Patients treated with deferiprone showed an improvement of more than 3 ms in cardiac T2* values, compared to an improvement of approximately 1 ms in patients treated with deferoxamine.

At the same time, FEV increased from baseline by 3.07 ± 3.58 in absolute units (%) in the deferiprone group, and by 0.32 ± 3.38 in absolute units (%) in the deferoxamine group (difference between groups; p = 0.003).

LA12-9907 study compared survival, incidence of cardiac disorders, and progression of cardiac disorders in 129 patients with thalassemia major treated for at least 4 years with deferiprone (N = 54) or deferoxamine (N = 75).

Cardiac effects were assessed by echocardiogram, electrocardiogram, New York Heart Association classification, and cardiac-related death.

During the first evaluation, no significant difference in the percentage of patients with cardiac disorders was demonstrated (13% for deferiprone compared to 16% for deferoxamine).

Among patients with cardiac problems at the first evaluation, no one treated with deferiprone experienced a worsening of their cardiac condition pa.

Like all medications, this medication can cause undesirable side effects, but they do not occur systematically in everyone.

The most serious undesirable effect of DEFERIPRONE ARROW 500 mg, scored film-coated tablet is a very significant reduction in the number of white (neutrophilic) blood cells.

This condition, called severe neutropenia or agranulocytosis, occurs in 1-2 people out of 100 who received deferiprone during clinical studies.

It may be associated with a serious infection, putting at risk the vital pro on.

If you develop infectious symptoms (fever, angina or flu-like symptoms), contact your doctor immediately.

Very common side effects (may affect more than in 10 people): abdominal pain nausea, vomiting, reddish/brown discoloration of urine.

In case of nausea or vomiting, it may be useful to take DEFERIPRONE ARROW 500 mg, film-coated tablet with food.

The coloring of urine is a very frequent effect without any consequences.

Common side effects (may affect 1-10 in 100 people): low number of white blood cells (agranulocytosis and neutropenia) headaches, diarrhea, increased number of liver enzymes, fatigue, increased appetite.

Frequency not known (cannot be estimated from the available data): allergic reactions, including irritation or rashes.

Manifestations of pain and joint swelling are associated with severe pain in one or more joints up to severe incapacity era.

In most cases, the pain disappears when treatment with deferiprone continues.

Neurological disturbances (e.g., tremors, difficulty walking, double vision, involuntary muscular contractions, respiratory problems) movement coordination problems) have been reported in children who were deliberately prescribed more than double the recommended maximum dose of 100 mg / kg / day for several years and has also been observed in children treated with standard referral doses.

For these children, these symptoms disappeared after stopping deferiprone.

If you experience any side effects, tell your doctor or pharmacist.

This also applies to any side effects that are not mentioned in this leaflet.

You can also report adverse effects directly via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and network of Regional Pharmacovigilance Centers.

• Website: /

By reporting side effects, you can help provide more information about the safety of the medicine.

Never take DEFERIPRONE

ARROW 500 mg, scored film-coated tablet: if you are allergic to deferiprone or one of the other ingredients contained in this medicine, mentioned in section 6

Talk to your doctor or pharmacist before taking DEFERIPRONE ARROW 500 mg, scored film-coated tablet.

The most serious side effect that may occur when taking DEFERIPRONE ARROW 500 mg, scored film-coated tablet is a very low number of white blood cells (neutrophils).

This condition, known as severe neutropenia or agranulocytosis, was seen in 1-2 in 100 people taking deferiprone in clinical studies.

Since white blood cells help fight infections, a low neutrophil count can put you at risk of developing a serious, life-threatening infection.

To monitor neutropenia, your doctor will ask you to take a blood test (to monitor your white blood cell count) regularly, as often as every week, for the duration of your treatment with DEFERIPRONE ARROW 500 mg, scored film-coated tablet.

It is very important for you to keep these appointments.

Please refer to the patient reminder card attached to this leaflet.

If you have symptoms of infection such as fever, sore throat, or flu-like symptoms, seek medical attention immediately.

Your white blood cell count should be checked within 24 hours to detect possible agranulocytosis.

If you are

HIV positive for the human immunodeficiency virus (HIV) or have liver or kidney dysfunction, your doctor may order additional tests.

Your doctor will also order tests to monitor your iron load.

Finally, he will ask you to undergo liver biopsies.

Other medicines and DEFERIPRONE

ARROW 500 mg, scored film-coated tablet

Inform your doctor or pharmacist if you are taking, have recently taken, or can take any other medication, including medication obtained without a prescription.

Do not take aluminum-based antioxidants at the same time as your treatment with DEFERIPRONE ARROW 500 mg, film-coated scored tablet.

Please consult your doctor or pharmacist before taking vitamin C with DEFERIPRONE ARROW 500 mg, scored film-coated tablet.

ARROW 500 mg, scored film-coated tablet may be harmful to the unborn child when used in pregnant women.

ARROW 500 mg, film-coated scored tablet should not be used during pregnancy unless absolutely necessary.

If you are pregnant or become pregnant during treatment with DEFERIPRONE ARROW 500 mg, scored film-coated tablet, seek medical advice immediately.

It is recommended that both women and men take special precautions during any sexual activity when it could lead to pregnancy.

Women of childbearing age are recommended to use effective contraception during treatment with DEFERIPRONE ARROW 500 mg, film-coated scored tablet and for 6 months after the last dose.

Men are recommended to use effective contraception during treatment and for 3 months after the last dose.

This should be discussed with your doctor.

Do not use DEFERIPRONE

ARROW 500 mg, scored film-coated tablet if you are breastfeeding.

Please see the patient reminder card attached to this note.

Not applicable.

Deferiprone is contraindicated in patients with known hypersensitivity to deferiprone or to any of the excipients in the formulations.

The following reactions have been reported in association with the administration of deferiprone: Henoch-Schönlein purpura; urticaria; and periorbital edema with skin rash.

Hypersensitivity to deferiprone or to any of the excipients in the formulations.

Deferiprone tablets are available in two formulations.

A 1,000 mg formulation and a 500 mg formulation, which have different dosing regimens to achieve the same total daily dosage.

To prevent medication errors, before prescribing and dispensing, ensure that the tablet formulation is appropriate for the dosing regimen.

Each tablet has distinct identifying characteristics.

Deferiprone tablets (three times a day), 1,000 mg: Starting oral dosage: 75 mg/kg/day (actual body weight) in three divided doses Maximum oral dosage: 99 mg/kg/day (actual body weight) in three divided doses Deferiprone tablets (three times a day), 500 mg: Starting oral dosage: 75 mg/kg/day (actual body weight) in three divided doses Maximum oral dosage: 99 mg/kg/day (actual body weight) in three divided doses 2.1 Important Dosage and Administration Information Deferiprone tablets are available in a 1,000 mg formulation and a 500 mg formulation, which have different oral dosing regimens to achieve the same total daily dosage.

Deferiprone tablets (three times a day).

• given three times a day Deferiprone tablets.

• given three times a day To prevent medication errors, before prescribing and dispensing, ensure that the tablet formulation is appropriate for the dosing regimen.

For patients who have trouble swallowing tablets, consider the use of oral solution.

Due to the risk of agranulocytosis, monitor ANC before and during deferiprone therapy.

ANC prior to start of deferiprone therapy and monitor on the following schedule during treatment: First six months of therapy: Monitor ANC weekly; Next six months of therapy: Monitor ANC once every two weeks; After one year of therapy: Monitor ANC every two to four weeks (or at the patient's blood transfusion interval in patients that have not experienced an interruption due to any decrease in ANC. Due to the risk of hepatic transaminase elevations, monitor ALT before and monthly during deferiprone therapy. Due to the risk of zinc deficiency, monitor zinc levels before and regularly during deferiprone therapy. 2.3 Recommended Dosage for 1,000 mg Deferiprone Tablets (three times a day) for Adult Patients with Transfusional Iron Overload due to Thalassemia Syndromes Starting Dosage for Three Times a Day Tablets The recommended starting oral dosage of deferiprone tablets (three times a day) is 75 mg/kg/day (actual body weight), in three divided doses per day. Table 3 describes the number of deferiprone tablets (three times a day) needed to achieve the 75 mg/kg/day total starting dosage).

Round dose to the nearest 500 mg (half-tablet).

Table 3: Number of Deferiprone 1,000 mg Tablets (three times a day) Needed to Achieve the Total Starting Daily Dosage of 75 mg/kg (rounded to the nearest half-tablet) Body Weight (kg) Morning Midday Evening 20 0.5 0.5 0.5 30 1 0.5 1 40 1 1 1 50 1.5 1 1.5 60 1.5 1.5 1.5 70 2 1.5 2 80 2 2 2 90 2.5 2 2.5 To minimize gastrointestinal upset when first starting therapy, dosing can start at 45 mg/kg/day and increase weekly by 15 mg/kg/day increments until the full prescribed dose is achieved.

Dosage Adjustments for Three Times Daily Tablets Tailor dosage adjustments for deferiprone tablets (three times a day) to the individual patient's response and therapeutic goals (maintenance or reduction of body iron burden).

The maximum oral dosage is 99 mg/kg/day (actual body weight), in three divided doses per day. Table 4 describes the number of deferiprone tablets (three times a day) needed to achieve the 99 mg/day total maximum daily dosage.

Table 4: Number of Deferiprone 1,000 mg Tablets (three times a day) Needed to Achieve the Maximum Total Daily Dosage of 99 mg/kg (rounded to the nearest half-tablet) Body Weight (kg) Morning Midday Evening 20 0.5 0.5 1 30 1 1 1 40 1.5 1 1.5 50 1.5 1.5 2 60 2 2 2 70 2.5 2 2.5 80 2.5 2.5 3 90 3 3 3 Pediatric use information is approved for Chiesi USA, Inc.'s FERRIPROX® (deferiprone) tablets.

However, due to Chiesi USA, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 2.4 Recommended Dosage for 500 mg Deferiprone Tablets (three times a day) for Adult Patients with Transfusional Iron Overload due to Thalassemia Syndromes Starting Dosage for Three Times a Day Tablets The recommended starting oral dosage of deferiprone tablets (three times a day) is 75 mg/kg/day (actual body weight), in three divided doses per day. Table 5 describes the number of deferiprone tablets (three times a day) needed to achieve the 75 mg/kg/day total starting dosage.

Round dose to the nearest 250 mg (half-tablet).

Table 5: Number of Deferiprone 500 mg Tablets (three times a day) Needed to Achieve the Total Starting Daily Dosage of 75 mg/kg dose (rounded to the nearest half-tablet) Body Weight (kg) Morning Midday Evening 20 1 1 1 30 1.5 1.5 1.5 40 2 2 2 50 2.5 2.5 2.5 60 3 3 3 70 3.5 3.5 3.5 80 4 4 4 90 4 4 4 To minimize gastrointestinal upset when first starting therapy, dosing can start at 45 mg/kg/day and increase weekly by 15 mg/kg/day increments until the full prescribed dose is achieved.

Tailor dosage adjustments for deferiprone tablets (three times a day) to the individual patient's response and therapeutic goals (maintenance or reduction of body iron burden).

The maximum oral dosage is 99 mg/kg/day (actual body weight), in three divided doses per day. Table 6 describes the number of deferiprone tablets (three times a day) needed to achieve the 99 mg/day total maximum daily dosage.

Table 6: Number of Deferiprone 500 mg Tablets (three times a day) Needed to Achieve the Maximum Total Daily Dosage of 99 mg/kg dose (rounded to the nearest half-tablet) Body Weight (kg) Morning Midday Evening 20 1.5 1 1.5 30 2 2 2 40 3 2 3 50 3.5 3 3.5 60 4 4 4 70 5 4.5 4.5 80 5.5 5 5.5 90 6 6 6 Pediatric use information is approved for Chiesi USA, Inc.'s FERRIPROX® (deferiprone) tablets.

However, due to Chiesi USA, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 2.5 Monitoring Ferritin Levels to Assess Efficacy Monitor serum ferritin concentration every two to three months to assess the effect of deferiprone on body iron stores.

If the serum ferritin is consistently below 500 mcg/L, consider temporarily interrupting deferiprone therapy until serum ferritin rises above 500 mcg/L. 2.6 Dosage Modification for Drug Interactions Allow at least a 4-hour interval between administration of deferiprone and other drugs or supplements containing polyvalent cations such as iron, aluminum, or zinc.

Tablets (three times a day), 1,000 mg White, film-coated, oval shaped tablets; imprinted with "T" score "1 K" on one side and plain on the other.

The tablets can be broken in half along the score line.

They are provided in

HDPE bottles. 1,000 mg film-coated tablets, 50 tablets NDC 51672-4237-4 Keep the bottle tightly closed to protect from moisture.

Store at 20°C to 25°C (68°F to 77°F) ; .

Tablets, 500 mg White to pinkish-white, capsule-shaped tablets; scored on one side, engraved "T" on the left of the score line and "5" on the right and plain on the other side.

They are provided in a 100 count HDPE bottle with a child-resistant cap. 500 mg tablets, 100 tablets NDC 51672-4196-1 Store at 20° to 25°C (68° to 77°F) .

Store at 20°C to 25°C (68°F to 77°F) ; .

In animal reproduction studies, oral administration of deferiprone to pregnant rats and rabbits during organogenesis at doses 33% and 49%, respectively, of the maximum recommended human dose (MRHD) resulted in structural abnormalities, embryo-fetal mortality and alterations to growth.

The limited available data from deferiprone use in pregnant women are insufficient to inform a drug-associated risk of major birth defects and miscarriage.

Based on evidence and developmental toxicity in animal studies, deferiprone can cause fetal harm when administered to a pregnant woman.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and of miscarriage is to 4% and to 20%, respectively.

Post-marketing data available from 39 pregnancies of deferiprone-treated patients and 10 pregnancies of partners of deferiprone-treated patients are as follows: Of the 39 pregnancies in deferiprone-treated patients, 23 resulted in healthy newborns, 6 ended in spontaneous abortion, 9 had unknown outcomes, and 1 infant was born with anal atresia, nephroptosis, ventricular septal defect, hemivertebra and urethral fistula.

Of the 10 pregnancies in partners of deferiprone-treated patients, 5 resulted in healthy newborns, 1 resulted in a healthy newborn with slight hypospadias, 1 was electively terminated, 1 resulted in the intrauterine death of twins, and 2 had unknown outcomes.

During organogenesis, pregnant rats and rabbits received deferiprone at oral doses of 0, 30, 80 or 200 mg/kg/day, and 0, 10, 50, or 150 mg/kg/day, respectively.

The daily dose was administered as two equal divided doses approximately 7 hours apart.

Doses of 200 mg/kg/day in rats and 150 mg/kg/day in rabbits, approximately 33% and 49% of the MRHD, respectively, resulted in increased post-implantation loss and reduced fetal weights in the presence of maternal toxicity (reduced maternal body weight and body weight gain in both rats and rabbits; abnormal large placenta at low incidence in rats).

The 200 mg/kg/day dose in rats resulted in external, visceral and skeletal fetal malformations such as cranial malformations, cleft palate, limb malrotation, anal atresia, internal hydrocephaly, anophthalmia and fused bones.

The dose of 150 mg/kg/day in rabbits resulted in external fetal malformations (partially opened eyes) and minor blood vessel and skeletal variations.

In rats, malformations including micrognathia and persistent ductus arteriosus could be observed in the absence of maternal toxicity at doses equal to or greater than and 80 mg/kg/day, approximately 5% and 13% of the MHRD, respectively.

Safety and effectiveness of deferiprone tablets have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 8 years of age.

Pediatric use information is approved for Chiesi USA, Inc.'s FERRIPROX® (deferiprone) tablets.

However, due to Chiesi USA, Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.

Clinical studies of deferiprone did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.